The Structure of the Nucleosomal DNA Repair Intermediate Affects the HPF1-Independent Automodification Activity of PARP2

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Tatyana A. Kurgina¹, Danil M. Shtanov^1,2, Mikhail M. Kutuzov¹, Nina A. Moor¹, and Olga I. Lavrik^1,a*

¹Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia

²Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia

^* To whom correspondence should be addressed.

Received: November 12, 2025; Revised: December 24, 2025; Accepted: February 1, 2026

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DNA-dependent nuclear enzymes poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2) are involved in the regulation of multiple DNA repair pathways, including base excision repair (BER). After activation by binding to damaged DNA, these enzymes synthesize negatively charged poly(ADP-ribose) (PAR) and covalently attach to amino acid residues of target proteins, including PARPs themselves. PARP2 activity is influenced by the nature of DNA lesion; for example, it is efficiently stimulated by DNA breaks flanked by phosphate group. However, it remains unclear which stages of the auto-PARylation reaction are most sensitive to the structure of damaged DNA. In this study, we investigated how PARP2 activity depends on the presence and position of a single-nucleotide gap in DNA (either free or in the context of nucleosome) at different stages of the automodification reaction conducted in the absence of the histone PARylation factor HPF1. The obtained results suggest that the presence of the gap affects the affinity of PARP2 for DNA/nucleosomes, thereby determining the number of catalytically active enzyme molecules and the efficiency of PARylation initiation. In contrast, PAR elongation was affected by the lesion location in the DNA/nucleosome structure, namely, its distance from the blunt DNA ends, and the environment of histone tails. Therefore, the damaged DNA structure can influence both the amount and the length of PAR synthesized by PARP2.

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KEY WORDS: poly(ADP-ribosyl)ation, PARP2, nucleosome, DNA repair, BER

DOI: 10.1134/S0006297925603995

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